Transdermal therapeutic system comprising a reservoir type pressure sensitive adhesive layer and a back layer with uni-directional resilience

ABSTRACT

A transdermal therapeutic system (TTS), in particular a patch, is described, comprising:
         a detachable protective layer;   a pressure-sensitive adhesive reservoir layer; and   a backing layer with or without a coating of pressure-sensitive adhesive and featuring a unidirectionally, preferably longitudinally, elastic material having an elasticity of at least 20%. The TTS is particularly suitable for use as a multi-day plaster for the treatment of, for instance, pain or drug dependency.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of application Ser. No.09/486,266, filed May 3, 2000 (now U.S. Pat. No. 6,814,976 issued onNov. 9, 2004), which is the National Stage of International ApplicationNo. PCT/EP98/05321 filed Aug. 21, 1998.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to a transdermal therapeutic system, in particularan active substance patch, comprising a detachable protective layer, apressure-sensitive reservoir layer and a backing layer with or without acoating of pressure-sensitive adhesive. The invention also relates to aprocess for producing such a transdermal therapeutic system(occasionally abbreviated to TTS below) and to the use thereof.

2. Description of the Prior Art

A TTS is a skin-applied administration form for active substances fordelivery through the skin, and has the appearance of traditionalpatches. It ought to be distinguished from a topical active substanceplaster, for example, a rheumatism plaster or a corn plaster. A TTS ofthis kind can include one or more active substances which are deliveredcontinuously over a fixed period at a predetermined rate to the site ofapplication. (“Heilman Klaus: Therapeutische Systeme—Konzept undRealisation programmierter Arzneiverabreichung” (Therapeuticsystems—Design and implementation of programmed drug administration),4^(th) edition, 1984, Ferdinand-Enke-Verlag, Stuttgart). The fixedperiod referred to above is usually 24 hours. For the treatment ofchronic disorders, however, it is necessary to administer medicamentsfor a longer period. It may therefore be appropriate to apply a TTS fora period longer than 24 hours, since this is more likely to result inconstant plasma levels.

A typical transdermal therapeutic system in the form of a patch is knownfrom EP-B 0 430 019. It has a backing layer which is impermeable to theactive substance, a pressure-sensitive adhesive reservoir layer, and adetachable protective layer. The active-substance-impermeable backinglayer can be composed of a flexible or inflexible material. Materialssuch as polymer films, metal foils, or a composite comprising a filmwhich has been coated with aluminum by vapour deposition may be employedas the backing layer. Where such systems are worn on the skin for aprolonged period, in particular for treating chronic disorders, therelative rigidity of the TTS causes a pronounced sensation of a foreignbody on the skin within a short period of time. This is extremelyunpleasant for the user.

Another embodiment of such a TTS is described in U.S. Pat. No.5,246,705. The transdermal system it describes has an elastomericbacking layer having a defined vapour transmission rate in the rangefrom 0.1 to 20 g/m²/hr and a Young's modulus in the range of about 10⁴to 10⁹ dynes/cm². Particularly, preferred materials for the elastomericbacking layer are, for example, A-B-A block copolymers, the A blockscomprising styrene and the B blocks comprising saturated hydrocarbonpolymers such as, for instance, ethylene-butylene copolymers,ethylene-propylene copolymers, and the like. When the transdermaltherapeutic systems as per U.S. Pat. No. 5,246,705 are worn on the skinfor a prolonged period, it is impossible to avoid the above-describedsensation of a foreign body.

U.S. Pat. No. 4,780,168 discloses a strip-like wound bandage for sealingwounds, which is fabricated from a woven or non-woven polymer-basedmaterial having a planar stretching characteristic in the range from 0.5to 110 (pounds/inch). Materials of such extensibility are, however, notimmediately suitable as materials for backing layers of transdermaltherapeutic systems. Either their extensibility is too low, in whichcase the aforementioned unpleasant foreign-body sensation is felt whenthe systems are worn on the skin for a prolonged period, or else theyare much too extensible, in which case the production of transdermaltherapeutic systems is accompanied by the curling effect, which isexplained below.

During the production of the laminate from which the individual activesubstance patches are punched, the material for the backing layer comesunder tensile stress and the resulting elastic return force means that,during punching, the opposite ends of the patches are each bent up.Because of the reject rate during the manufacturing process, the curlingeffect results in high costs, as well as unnecessary environmentalburdens.

Aside from the abovementioned disadvantages, a material for the backinglayer of a wound bandage is also unsuited to a TTS for other reasons,such as the required impermeability to the active substance.

The object of the invention is therefore to provide a transdermaltherapeutic system which comprises a detachable protective layer, apressure-sensitive adhesive reservoir layer and a backing layer with orwithout a coating of pressure-sensitive adhesive and which avoids theaforementioned disadvantages. In particular, there should be nosensation of a foreign body on the skin in the course of prolongedwearing, even for periods of from several days to about 1 or 2 weeks.Furthermore, the production of the TTS should not be accompanied by thecurling effect, thus ensuring rational and inexpensive production.

This object is achieved in accordance with the invention by atransdermal therapeutic system, in particular an active substance patch,comprising a detachable protective layer, a pressure-sensitive adhesivereservoir layer and a backing layer with or without a coating ofpressure-sensitive adhesive, the backing layer being a unidirectionally,especially longitudinally, elastic material having an elasticity of atleast 20%.

Preferred embodiments of the TTS of the invention are the subject-matterof the dependent claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a plan view of the TTS of the invention according to thepresent invention.

FIG. 2 is a cross section made through plane II-II of the TTS as shownin FIG. 1.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the invention, the TTS features not only a detachableprotective layer and a pressure-sensitive adhesive layer but also abacking layer which, optionally, is coated with a pressure-sensitiveadhesive and which has a specifically defined unidirectional elasticity.With regard to the TTS of the present invention, the elasticity isdetermined in accordance with the DIN standards 60 000 and 61 632 (April1985), which are conventionally used for elasticity tests. Originally,these DIN standards applied to ideal bandages; however the horizontalforce extension unit used to test the elasticity can be employedanalogously for other materials as well. In accordance with theinvention, the backing layer of the TTS is elastic in only onedirection, i.e., in a longitudinal or a transverse direction. Relativeto the longitudinal axis of the TTS, the transverse axis is that lyingat a right angle to it. In a circular TTS, the longitudinal andtransverse axis are of course identical in length. In particular, thebacking layer material used in accordance with the invention isunidirectionally longitudinally elastic.

In the other direction, the backing layer is non-elastic. Non-elasticmeans that no elasticity can be found with testing by hand. In the caseof measurements in accordance with DIN 61 632 the elasticity is lessthat 20%. In accordance with the invention, therefore, the elasticity inone direction, mainly the elastic direction, is above 20%.

Since the production of the patch involves it being punched out from alaminate, it would also be possible to conceive in principle of the TTSbeing “unidirectionally” elastic at an angle to the longitudinaldirection of the patch. Oblique elasticity of this kind is, however, theresult of a superposition of elasticity in the transverse andlongitudinal directions.

In the TTS of the present invention, the elasticity of theundirectionally elastic material used for the backing layer ispreferably less than 150%. In a more preferred embodiment, theelasticity is in the range from 40% to 70%. The most preferredelasticity for a backing layer material, and, accordingly, that which ismost advantageous for the achievement of the object on which theinvention is based, lies within the range between 44% and 56%, alwaysmeasured in accordance with DIN 61 632.

Preferred materials for the unidirectionally elastic backing layer arethose which are microbially nondegradable. The material should be morethan 90%, preferably more than 99%, microbially nondegradable. Thedegradability can be measured by conventional methods familiar to theperson skilled in the art. Low degradability is particularly importantin the case of TTSs which are to be worn on the skin for a prolongedperiod. The reason for this is that, owing to the transpiration of theskin, a microclimate in which bacteria, fungi, spores, etc. absolutelythrive develops directly below the section of skin covered by the TTS.Consequently, low microbial degradability, especially in the case ofprolonged wearing, is extremely advantageous. The material of thebacking layer can be a woven fabric, a nonwoven fabric, or a film. Wherethe backing layer comprises a polymer, the said polymer is selectedadvantageously from polyethylene, polypropylene, or polyesters,especially polyalkylene terephthalates.

A number of polymeric materials may be mentioned by way of example forthe backing layer. Advantageous polymeric materials which meet the aboverequirement of low microbial degradability are polyterephthalic diestersobtainable by the reaction of a starting material selected from ethyleneglycol, 1,4-butanediol, 1,4-dihydroxymethycyclohexane, terephthalicacid, isophthalic acid, adipic acid, azelaic acid, sebacic acid,dimethyl terephthalate, dimethyl azelate, dimethyl sebacate, bisphenol Adiglycidyl ether, n-decane-1,10-dicarboxylic acid, polyethylene glycoland polybutylene glycol.

In the transdermal therapeutic system of the invention, it is likewisepossible for a further separating layer to be arranged between thebacking layer and the reservoir layer for the purpose, for example, ofpreventing active substance permeability. In this case, the backinglayer on the skin-facing side, and/or the separating layer on the distalside, are/is likewise coated with pressure-sensitive adhesive.

For the effectiveness of a TTS of the invention, it is advantageous forthe backing layer to project beyond the reservoir on all sides. This hasthe advantage that there are no losses of active substance in thelateral direction. Furthermore, the TTS of the invention can be producedin a particularly inexpensive manner since the sections containingactive substance can be punched separately. This avoids expensive,environmentally harmful, leftover waste pieces containing activesubstance. The backing layer of the TTS has a water vapour permeabilityof at least 0.1 g/m²/h, preferably from 1 to 20 g/m²/h.

Where a woven or nonwoven fabric or else a porous film is used, theporosity lies within the range from 10% to 50%. Porosity here means theproportion of pores having an area of less than or equal to 400 μm² as apercentage of the reference area in question. This relative pore areacan be determined by measuring and counting the pores of any unextendedreference area under the microscope or a thread counter.

If a woven fabric is used for the transdermal therapeutic system (TTS)of the invention, the backing layer has a number of warp threads in therange of 300-350, preferably in the range of 310-330, and/or a number ofweft threads in the range from 100 to 140, preferably in the range from120 to 130, measured in each case per 10 cm of unextended fabric.

The pressure-sensitive adhesive reservoir layer of the transdermaltherapeutic system of the invention comprises at least one activesubstance. This substance is preferably selected from the groupconsisting of psychopharmaceuticals, analgesics and hormones. Particularsubstances which may be considered include estradiol as a hormone andbuprenorphine as an analgesic. The psychopharmaceutical is preferably aparasympathomimetic. Particularly suitable parasympathomimetics are thefollowing:

-   1. choline esters, e.g. acetylcholine, bethanechol, carbachol, or    methacholine;-   2. alkaloids, e.g. arecoline and its derivatives, pilocarpine;-   3. choline esterase inhibitors, e.g. demacarium bromide, distigmine    bromide, neostigmine, physostigmine, pyridostigmine bromide,    galanthamine.    These substances can of course be used in combinations with one    another. The active substance content is particularly set so that    when the plaster is removed a pulloff effect occurs. This effect is    explained hereinbelow.

Where a TTS includes a backing layer of limited water vapourpermeability, such as a PET film, the skin is unable to give off watervapour at the application site while the TTS is being worn. This waterbecomes incorported in the skin. At the application site, therefore, thewater content is higher than the physiobiological norm. A substancewhich is difficult for the skin to absorb (such as buprenorphine, forexample) becomes incorporated into a deposit in the skin. When the TTSis pulled off, the skin gives off water vapour suddenly. As a result ofremoval of this water vapour, there is a sudden increase in theconcentration of the medicament to above the saturation concentration,since solvent is removed. A stable state is reached by the rapidemptying of the skin deposit. Therefore, as a result of the TTS beingpulled off, there is a rapid increase in the plasma concentration of theactive substance. The utilization of the pulloff effect is preferred forbetter utilization of active substance. In accordance with the presentinvention, therefore, the concentration of the active substance is setsuch that the abovementioned pulloff effect comes about.

The absolute level of active substance for achieving the pulloff effectcannot generally be defined validly with precision. It varies from oneactive substance to another and also depends on the embodiment of theTTS. Setting of the level can, however, be undertaken by the personskilled in the art without undue burden by means of routine experiments.In the case of buprenorphine, the level is about 5-15% by weight.

The pressure-sensitive adhesive reservoir layer may also include awater-absorbing polymer. In one preferred embodiment, thewater-absorbing polymer is a polyvinylpyrrolidone. Thepolyvinylpyrrolidone preferably has a molecular weight in the range from1×10³ to 2×10⁶. Such polyvinylpyrrolidones include Kollidon®.

For special purposes, moreover, such as for use in hospitals with manypatients or for use in double blind studies where TTS containing activesubstance are compared with placebo TTS, it is preferred for the side ofthe TTS that faces outwards, that is, away from the skin, to carry inthe backing layer a marking/control element which is differentiated fromthe remaining area.

This element can differ from the remaining portion of the backing layerin its structure or in other properties, such as elasticity or porosity.By means of such a marking/control element the properties of the backinglayer can be made different. For example, the elasticity of such anelement can be greater than the elasticity of the remaining portion ofthe backing layer. If such a marking/control element is specificallyincorporated in one portion of the backing layer, then its relativeelasticity, where desired, is preferably within a range situated about20% below or about 20% above the elasticity of the remaining portion ofthe backing layer.

The marking/control element can also serve to distinguish the individualTTSs from one another in terms of their active substance content. Thisis done preferably by means of coloured marking, for example by means ofa coloured thread or stripe. This is particularly advantageous if theTTS has to be held ready in large quantities at different dosages at onelocation: for example, a hospital with large numbers of patients.

Because of its backing layer, the transdermal therapeutic system of theinvention is particularly suitable for use as a multi-day plaster. Thebacking layer is tailored to this requirement. Thus it can be used inparticular to treat chronic pain or else to treat drug dependency.

The TTS of the present invention is produced by means of conventionalprocesses. In general, such a process comprises the steps of producingthe individual TTSs by punching from a presupplied strip-like laminatecomprising the unidirectionally elastic backing layer of the invention,an active substance layer and a detachable layer.

In one particularly preferred process for producing the TTS of theinvention, the above steps are modified to the effect that, in apresupplied strip-like laminate having an optionally pressure-sensitiveadhesive, unidirectionally elastic backing layer and a detachableprotective layer, pressure-sensitive adhesive active substance reservoirsections are inserted in sequence in the longitudinal direction, and thebacking layer is separated by punching. Lastly, the protective layer inthe spaces between the active substance reservoir sections is separated.This specific process is highly advantageous from both economic andenvironmental standpoints. Indeed, the separate insertion of the activesubstance reservoir sections avoids the formation of waste comprisingactive substance (which is usually very expensive) and thus the need todispose, again at a great expense, of such waste. A similar process isdescribed in DE-B 41 10 027, which is expressly incorporated herein byreference.

The invention is elucidated below with reference to a drawing and anexemplary embodiment.

Referring now to FIG. 1, a plan view of a TTS of the present inventionis shown and referred to generally at numeral 10. Lying atop thedetachable protective layer 12 is the backing layer 20, which is coatedwith a pressure-sensitive adhesive devoid of active substance. Forexemplary purposes, detachable protective layer 12 is shown asrectangular. The backing layer has the form of a rectangle with roundedcorners 24. The punching line 12 a outlines the form of the backinglayer 20. It extends outside the laminate comprising the reservoir 14and, optionally, a barrier or separating layer 16. The course of thepunching line 12 a means that loss of active substance is avoided whenthe TTS 10 is punched out. Within the backing layer 20 it is possible tomake out the contours of the reservoir 14 and of the optional barrier orseparating layer 16.

In the TTS shown, with the unidirectionally elastic backing layer 20,the the backing layer 20 protrudes beyond the abovementioned laminatecomprising the reservoir 14 on all sides. The reservoir 14 is preferablyrectangular in form. The rectangular from is preferred since it preventsactive substance loss when the reservoir is cut.

Referring now to FIG. 2, a cross section through plane II-II of FIG. 1is shown. For clarity, the thickness of the layers have beenexaggerated. The TTS 10 features the reservoir 14, the removableprotective layer 12, the optional barrier layer 16, and a further layer18 of pressure-sensitive adhesive devoid of active substance. This layer18 is necessary when a barrier layer 16 is present. In this depictedembodiment, the backing layer 20 and the pressure-sensitive adhesivelayer 18 devoid of active substance protrude beyond the abovementionedlaminate on all sides.

EXAMPLES

In order to produce the unidirectionally elastic backing layer of thepresent invention, a woven polyester fabric having the followingfeatures was produced by means of the techniques known to the personskilled in the art.

TEST FEATURES UNIT Nominal MIN MAX X WIDTH OF MATERIAL mm 1500 1300 13901360 BASIS WEIGHT g/m² 100 95 103 100 (unextended) (DIN 53854 + (DIN53884) EXTENSION (longitudinal) % — — — — (transverse) % 50 46 52 48(DIN 61632) NUMBER OF WARP 320 310 330 324 THREADS Per 10 cm unextendedNUMBER OF WEFT 125 124 126 124 THREADS Per 10 cm unextendedIn addition 49.175 kg of Durotak type 387-2054 (48.3% by weightsolution), 4.450 kg of melted laevulinic acid, and 6.675 kg of oleyloleate were homogenized with stirring. Then, 4.450 kg of Kollidon 90 Fwere added in portions. Following dilution with 6.800 kg of ethanol, themixture was stirred at 170-190 rpm for 5 hours. Then, 4.450 kg ofbuprenorphine base, suspended in 4.500 kg of ethyl acetate, was added.The mixture was diluted with 4.500 kg of ethyl acetate.

The mixture was stirred at 170 rpm for about 7 hours. It was then testedfor homogeneity. When the composition was homogenous it wasdevolatilized, with the stirrer switched off.

Following homogenization, the adhesive composition was applied to asiliconized polyester film. The organic solvents were removed by dryingat normally 35° C. to 80° C. The laminate, comprising siliconizedpolyester film and buprenorphine-containing pressure-sensitive adhesivelayer, was subsequently covered with a second polyester film 23 μmthick.

The siliconized polyester film was removed from the resulting activesubstance laminate. Subsequently, rectangles measuring 50 cm² werepunched out and were placed with their adhering face, at intervals of 3cm, onto the siliconized fave of a further 100 μm polyester protectivefilm. Atop these reservoir sections was placed the unidirectionallyelastic, woven polyester fabric, which in this case was likewise coatedwith pressure-sensitive adhesive. Subsequently, individuallongitudinally elastic patches were punched out. A wearing test wasconducted on n=10 subjects using this TTS of the invention.

Comparative Example 1

In this example, a bidirectionally elastic woven polyester fabric wasused instead of the unidirectionally elastic woven polyester fabric ofthe invention. The extensibility of this fabric (longitudinal andtransverse extension) was 30% as measured in accordance with DIN 61 632.Its basis weight was 109 g/m². This material was a polyethyleneterephthalate. In other respects, the TTSs produced in accordance withthis comparative example were the same as those of the inventiveexample.

Using the TTSs according to this comparative example, a wear test waslikewise conducted on n=10 subjects.

Comparative Example 2

TTSs were prepared in accordance with Example 1 and Comparative Example1 but using a rigid polyester film (15 μm thick) of Hostaphan®RN 15,Hoechst AG, coated with pressure-sensitive adhesive, instead of aunidirectionally or bidirectionally elastic backing layer, respectively.In this case as well, a wear test was carried out with the resultingTTSs on n=10 subjects.

Evaluation

The comparative wear test of the TTSs of Example 1, Comparative Example1 and Comparative Example 2 gave the following result.

When polyester film was used as the backing layer (Comparative Example2), a sensation of a foreign body occurred on the very first day. On thesecond day, creasing occurred and, beginning on the third day, the TTSbecame detached. The TTS of Example 1 and that of Comparative Example 1were torn without problems by all 10 subjects, with no sensation of aforeign body, with no impairment of bond strength, and, furthermore,with no skin irritations, for at least seven days. In respect of wearcomfort, therefore, the TTS of Example 1 and that of Comparative Example1 are approximately equal. However, with regard to the production of theTTS of Comparative Example 1, complications in production occurred in afrequency of more than 50%, these complications being attributablepredominantly to the curling effect.

1. A transdermal therapeutic system comprising: a detachable protectivelayer; a pressure-sensitive adhesive reservoir layer comprising at leastone active substance; and a backing layer being elastic in only onedirection, comprising unidirectional elastic material having anelasticity of at least 20% and less than 150%, wherein the material is awoven fabric having a number of warp threads in the range of 300 to 350and a number of weft threads in the range of 100 to 140, the number ofwarp threads and the number of weft threads being measured per 10 cm ofunstretched fabric, said fabric comprising pores for water vaporpermeability having a size less than or equal to 400 μm² embracing anareal proportion of between 10% and 50% of said fabric.
 2. Thetransdermal therapeutic system of claim 1 wherein the backing layer isprovided with or without a coating of pressure-sensitive adhesive. 3.The transdermal therapeutic system of claim 2 further comprising aseparating layer between the reservoir layer and the backing layer. 4.The transdermal therapeutic system of claim 1 wherein the system is apatch.
 5. The transdermal therapeutic system of claim 1 wherein thebacking layer comprises longitudinally elastic material.
 6. Thetransdermal therapeutic system of claim 1 wherein the backing layerprojects beyond the reservoir layer on all sides.
 7. The transdermaltherapeutic system of claim 1 wherein the elastic material of thebacking layer has an elasticity of between 20-80%.
 8. The transdermaltherapeutic system of claim 7 wherein the elastic material of thebacking layer has an elasticity of between 40-70%.
 9. The transdermaltherapeutic system of claim 8 wherein the elastic material of thebacking layer has an elasticity of between 44-56%.
 10. The transdermaltherapeutic system of claim 1 wherein the elastic backing layer is morethan 90% microbially nondegradable.
 11. The transdermal therapeuticsystem of claim 10 wherein the elastic backing layer is more than 99%microbially nondegradable.
 12. The transdermal therapeutic system ofclaim 1 wherein the backing layer comprises a material selected from thegroup consisting of a polyethylene, a polypropylene and a polyester. 13.The transdermal therapeutic system of claim 12 wherein the backing layercomprises a polyalkylene terephthalate.
 14. The transdermal therapeuticsystem of claim 13 wherein the backing material is a polyterephthalicdiester.
 15. The transdermal therapeutic system of claim 14 wherein thebacking material is a polyterephthalic acid diol ester obtainable by thereaction of a starting material selected from the group consisting ofethylene glycol, 1,4-butanediol, 1,4-dihydroxymethylcyclohexane,terephthalic acid, isophthalic acid, adipic acid, azelaic acid, sebacicacid, dimethyl terephthalate, dimethyl azelate, dimethyl sebacate,bisphenol A diglycidyl ether, n-decane-1, 10-dicarboxylic acid,polyethylene glycol, and polybutylene glycol.
 16. The transdermaltherapeutic system of claim 1 wherein the reservoir layer comprises atleast one active substance selected from the group consisting of apsychopharmaceutical, an analgesic and a hormone.
 17. The transdermaltherapeutic system of claim 16 wherein the active ingredient is selectedfrom the group consisting of oestriol, buprenorphine and aparasympathomimetic.
 18. The transdermal therapeutic system of claim 17,wherein the parasympathomimetic active ingredient is selected from thegroup consisting of choline esters, alkaloids and choline esteraseinhibitors.
 19. The transdermal therapeutic system of claim 18, whereinthe choline esters are selected from the group consisting ofacetylcholine, bethanechol, carbachol and methacholine.
 20. Thetransdermal therapeutic system of claim 18, wherein the alkaloids areselected from the group consisting of arecholine and its derivatives andpilocarpine.
 21. The transdermal therapeutic system of claim 18, whereinthe choline esterase inhibitors are selected from the group consistingof demacarium bromide, distigmine bromide, neostigmine, physostigmine,pyridostigmine bromide and galanthamine.
 22. The transdermal therapeuticsystem of claim 18 wherein the parasympathomimetic active ingredientsare used in combination with each other.
 23. The transdermal therapeuticsystem of claim 1 wherein the backing layer facing outwardly has adifferentiated marking element.
 24. The transdermal therapeutic systemof claim 23 wherein the marking element is a colored marking.
 25. Thetransdermal therapeutic system of claim 24 wherein the colored markingis in strip form or a colored thread.
 26. The transdermal therapeuticsystem of claim 23 wherein the marking element has an elasticity ofbetween −20% to +20% relative to the elasticity of the remaining portionof the backing layer.
 27. The transdermal therapeutic system of claim 1wherein the backing layer has a water vapor permeability of at least 0.1g/m²/h.
 28. The transdermal therapeutic system of claim 27 wherein thebacking layer has a water vapor permeability of between 1 to 20 g/m²/h.29. The transdermal therapeutic system of claim 1 wherein the backinglayer has a number of warp threads in the range from 310 to 330 per 10cm of unstretched fabric.
 30. The transdermal therapeutic system ofclaim 1 wherein the number of weft threads is in the range from 120 to130 per 10 cm of unstretched fabric.